PB2051: POPULATION PHARMACOKINETIC/PHARMACODYNAMIC/EFFICACY MODELING OF SB12 (PROPOSED ECULIZUMAB BIOSIMILAR) AND REFERENCE ECULIZUMAB
Authors: Hyuna Lee, Jihye Park, Hyerin Jang, Jungryul Kim
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Soliris, reference eculizumab, is a humanized monoclonal antibody that is derived from the murine anti-human C5 antibody m5G1.1, which binds to the terminal complement protein C5, thereby inhibiting its cleavage into C5a and C5b during complement activation to decrease the formation of terminal complement complex which is known to lyse red blood cells rapidly. SB12 is a proposed biosimilar product of reference eculizumab (ECU). The Phase I study has demonstrated comparable pharmacokinetic (PK), pharmacodynamic (PD), and safety of SB12 and ECU in healthy subjects, and the Phase III study has proved comparable clinical efficacy, safety, PK, and PD of SB12 and ECU in paroxysmal nocturnal hemoglobinuria (PNH) patients. To our knowledge, no population PK/PD/efficacy model for ECU using pooled data of healthy subjects and PNH patients has been reported. Aims: The purpose of the modeling is to describe PK, PD, and efficacy of SB12 and ECU, compare similarity of PK, PD, and efficacy profiles between SB12 and ECU, and find clinically significant covariate relationships. Methods: The PK, PD (terminal complement activity) and efficacy (lactate dehydrogenase [LDH]) data of SB12 and ECU were obtained from Phase I study (a total of 240 healthy subjects administered with a single dose of 300 mg intravenous infusion), and Phase III study (49 patients with PNH given an initial dose of 600 mg weekly for first 4 weeks in induction phase followed by maintenance dose of 900 mg every 2 weeks). One- and two-compartment model with first-order elimination were tested for the serum concentration-time profiles of SB12 and ECU. For PD and efficacy models, both direct and indirect models were tested for the terminal complement activity-time and LDH-time profiles of SB12 and ECU. The inter-individual variability of each parameter was applied exponentially, and additive, proportional, or combined error models were evaluated for the residual variability. The covariate model was built in a stepwise fashion with forward inclusion and backward elimination. Population PK/PD/efficacy modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA) Results: The two-compartment model adequately described the PK properties of SB12 and ECU, and subject’s weight was chosen through covariate analysis as a clinically significant covariate affecting drugs’ clearance (CL) and central volume of distribution (Vc) as previously reported in literature. Treatment group was not a significant covariate affecting CL. The inhibitory sigmoid Emax model and the indirect response model well described the PK and PD relationship, and PK and efficacy relationship of SB12 and ECU, respectively. Through population PK/PD and PK/PD/efficacy modeling, the relationship between PK, PD, and efficacy was characterized, as well as the relationship between PD and efficacy. There were no differences in PK, PD, and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and patients with PNH. Summary/Conclusion: The population modeling showed PK/PD/efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12. Keywords: Clinical data, Monoclonal antibody, Paroxysmal nocturnal hemoglobinuria (PNH), Phase III